Senior Scholar Award in Global Infectious Disease
Towards Broad-spectrum Antivirals: Functional Screens for Nonessential and Antiviral Host Genes
Established and emerging viral diseases such as viral hepatitis, dengue fever, West Nile, yellow fever, Venezuelan, Western & Eastern equine encephalitis are major health concerns, particularly in developing countries. Preventative vaccines and effective treatments are not available for many of these diseases. New and more effective drugs are sorely needed to treat these viral infections.
The traditional path to antiviral development involves identifying a virus-specific target molecule, screening for inhibitors, and then refining lead compounds to improve potency, minimize toxicity, and maximize efficacy in animals and humans. Compounds developed by this process are often highly specific and due to viruses’ high mutation rate, new viral strains are continually emerging that are resistant to the effects of these very specific compounds. A largely unexplored area is the possibility of developing broad-spectrum antiviral drugs. The development of such drugs, while largely hypothetical, is very attractive from the standpoint of simplified clinical development and more practical aspects of treatment in the developing world.
The specific goals of this project are two-fold: (1) to identify cellular processes that are essential for replication of groups of viruses and (2) to identify cellular gene products that exhibit antiviral activities. For the first aim, we will use RNA interference to lower expression of non-essential mammalian genes to identify those that are required for efficient replication of diverse viruses. Follow-up studies will be conducted to understand the mechanism of action of selected cellular factors with the intent of eventually developing small molecules that can block steps essential for virus multiplication.
In the second project, we will focus on the myriad of cellular genes induced by type I and type II interferons, proteins that stimulate viral resistance in cells. More than 500 genes are modulated directly or indirectly through the interferon-induced signalling cascade to modify cells and produce viral resistant cells. Despite decades of study, we understand the functions of only a handful of these genes. We plan to conduct a comprehensive screen to identify interferon-induced genes that exhibit antiviral activity against a collection of mammalian viruses. By identifying specific genes that exhibit broad and effective antiviral activity and studying how they are regulated, we may be able to learn how to induce a specific antiviral state without using interferon which has a number of toxic side effects.